Slide-tags enables single-nucleus barcoding for multimodal spatial genomics

Nature, Journal Year: 2023, Volume and Issue: 625(7993), P. 101 - 109

Published: Dec. 13, 2023

Abstract Recent technological innovations have enabled the high-throughput quantification of gene expression and epigenetic regulation within individual cells, transforming our understanding how complex tissues are constructed 1–6 . However, missing from these measurements is ability to routinely easily spatially localize profiled cells. We developed a strategy, Slide-tags, in which single nuclei an intact tissue section tagged with spatial barcode oligonucleotides derived DNA-barcoded beads known positions. These can then be used as input into wide variety single-nucleus profiling assays. Application Slide-tags mouse hippocampus positioned at less than 10 μm resolution delivered whole-transcriptome data that indistinguishable quality ordinary RNA-sequencing data. To demonstrate applied human tissues, we performed assay on brain, tonsil melanoma. revealed cell-type-specific varying across cortical layers contextualized receptor–ligand interactions driving B cell maturation lymphoid tissue. A major benefit it adaptable almost any single-cell measurement technology. As proof principle, multiomic open chromatin, RNA T receptor (TCR) sequences same cells metastatic melanoma, identifying transcription factor motifs cancer state transitions distinct microenvironments. offers universal platform for importing compendium established genomics repertoire.

Language: Английский

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A TCF4-dependent gene regulatory network confers resistance to immunotherapy in melanoma

Cell, Journal Year: 2024, Volume and Issue: 187(1), P. 166 - 183.e25

Published: Jan. 1, 2024

To better understand intrinsic resistance to immune checkpoint blockade (ICB), we established a comprehensive view of the cellular architecture treatment-naive melanoma ecosystem and studied its evolution under ICB. Using single-cell, spatial multi-omics, showed that tumor microenvironment promotes emergence complex transcriptomic landscape. Melanoma cells harboring mesenchymal-like (MES) state, population known confer targeted therapy, were significantly enriched in early on-treatment biopsies from non-responders TCF4 serves as hub this landscape by being master regulator MES signature suppressor melanocytic antigen presentation transcriptional programs. Targeting genetically or pharmacologically, using bromodomain inhibitor, increased immunogenicity sensitivity ICB therapy. We thereby uncovered TCF4-dependent regulatory network orchestrates multiple programs contributes both therapy melanoma.

Language: Английский

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The epithelial–mesenchymal plasticity landscape: principles of design and mechanisms of regulation

Nature Reviews Genetics, Journal Year: 2023, Volume and Issue: 24(9), P. 590 - 609

Published: May 11, 2023

Language: Английский

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Cancer metastasis: Molecular mechanisms and clinical perspectives

Pharmacology & Therapeutics, Journal Year: 2023, Volume and Issue: 250, P. 108522 - 108522

Published: Sept. 1, 2023

Language: Английский

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Deciphering tumor ecosystems at super resolution from spatial transcriptomics with TESLA

Cell Systems, Journal Year: 2023, Volume and Issue: 14(5), P. 404 - 417.e4

Published: May 1, 2023

Cell populations in the tumor microenvironment (TME), including their abundance, composition, and spatial location, are critical determinants of patient response to therapy. Recent advances transcriptomics (ST) have enabled comprehensive characterization gene expression TME. However, popular ST platforms, such as Visium, only measure low-resolution spots large tissue areas that not covered by any spots, which limits usefulness studying detailed structure Here, we present TESLA, a machine learning framework for annotation with pixel-level resolution ST. TESLA integrates histological information annotate heterogeneous immune cells directly on histology image. further detects unique TME features tertiary lymphoid structures, represents promising avenue understanding architecture Although mainly illustrated applications cancer, can also be applied other diseases.

Language: Английский

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Reversible transitions between noradrenergic and mesenchymal tumor identities define cell plasticity in neuroblastoma

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: May 4, 2023

Abstract Noradrenergic and mesenchymal identities have been characterized in neuroblastoma cell lines according to their epigenetic landscapes core regulatory circuitries. However, relationship relative contribution patient tumors remain poorly defined. We now document spontaneous reversible plasticity between the two identities, associated with reprogramming, several models. Interestingly, xenografts cells from each identity eventually harbor a noradrenergic phenotype suggesting that microenvironment provides powerful pressure towards this phenotype. Accordingly, such is systematically observed single-cell RNA-seq of 18 tumor biopsies 15 PDX Yet, subpopulation these presents features are shared models, indicating described models has relevance patients. This work therefore emphasizes intrinsic properties dependent upon external cues environment drive identity.

Language: Английский

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Immune escape and metastasis mechanisms in melanoma: breaking down the dichotomy

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Feb. 14, 2024

Melanoma is one of the most lethal neoplasms skin. Despite revolutionary introduction immune checkpoint inhibitors, metastatic spread, and recurrence remain critical problems in resistant cases. employs a multitude mechanisms to subvert system successfully metastasize distant organs. Concerningly, recent research also shows that tumor cells can disseminate early during melanoma progression enter dormant states, eventually leading metastases at future time. Immune escape metastasis have previously been viewed as separate phenomena; however, accumulating evidence breaking down this dichotomy. Recent into progressive provides dedifferentiation similar classical epithelial mesenchymal transition (EMT), genes involved neural crest stem cell maintenance, hypoxia/acidosis, are important factors simultaneously metastasis. The likeness between EMT dissemination, differences, become apparent these contexts. Detailed knowledge behind “dual drivers” promoting metastatically inclined immunosuppressive environments yield novel strategies effective disabling multiple facets progression. Furthermore, understanding through drivers may provide insight towards treatments capable preventing arising from dissemination or improving immunotherapy outcomes.

Language: Английский

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Phenotype Switching and the Melanoma Microenvironment; Impact on Immunotherapy and Drug Resistance

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(2), P. 1601 - 1601

Published: Jan. 13, 2023

Melanoma, a highly heterogeneous tumor, is comprised of functionally diverse spectrum cell phenotypes and subpopulations, including stromal cells in the tumor microenvironment (TME). Melanoma has been shown to dynamically shift between different transcriptional states or phenotypes. This referred as phenotype switching melanoma, it involves quiescent proliferative cycle states, dramatic shifts invasiveness, well changes signaling pathways melanoma cells, immune composition TME. plasticity associated with altered gene expression cancer-associated fibroblasts, extracellular matrix, which drive metastatic cascade therapeutic resistance. Therefore, resistance therapy not only dependent on genetic evolution, but also suggested be driven by adaptive phenotypic plasticity. review discusses recent findings switching, immunotherapy resistance, balancing homeostatic TME subpopulations. We discuss future perspectives biology neural crest-like state(s) melanoma.

Language: Английский

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The mechanical phenotypic plasticity of melanoma cell: an emerging driver of therapy cross-resistance

Oncogenesis, Journal Year: 2023, Volume and Issue: 12(1)

Published: Feb. 11, 2023

Abstract Advanced cutaneous melanoma is the deadliest form of skin cancer and one most aggressive human cancers. Targeted therapies (TT) against BRAF mutated immune checkpoints blockade (ICB) have been a breakthrough in treatment metastatic melanoma. However, therapy-driven resistance remains major hurdle clinical management disease. Besides shaping tumor microenvironment, current treatments impact transition states to promote cell phenotypic plasticity intratumor heterogeneity, which compromise efficacy outcomes. In this context, mesenchymal-like dedifferentiated cells exhibit remarkable ability autonomously assemble their own extracellular matrix (ECM) biomechanically adapt response therapeutic insults, thereby fueling relapse. Here, we review recent studies that highlight mechanical as hallmark adaptive non-genetic emerging driver cross-resistance TT ICB. We also discuss how targeting BRAF-mutant ECM-based mechanotransduction pathways may overcome cross-resistance.

Language: Английский

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Disrupting cellular memory to overcome drug resistance

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Nov. 6, 2023

Abstract Gene expression states persist for varying lengths of time at the single-cell level, a phenomenon known as gene memory. When cells switch states, losing memory their prior state, this transition can occur in absence genetic changes. However, we lack robust methods to find regulators or track state switching. Here, develop lineage tracing-based technique quantify and identify that states. Applied melanoma without therapy, long-lived fluctuations are predictive later resistance targeted therapy. We also PI3K TGF-β pathways switching modulators. propose pretreatment model, first applying inhibitor modulate then which leads less than therapy alone. Together, present method finding modulators associated cell fates.

Language: Английский

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